Structural insights of key enzymes into therapeutic intervention against SARS-CoV-2.

COVID-19 pandemic, caused by SARS-CoV-2, has drastically affected human health all over the world. After the emergence of the pandemic the major focus of efforts to attenuate the infection has been on repurposing the already approved drugs to treat COVID-19 adopting a fast-track strategy. However, to date a specific regimen to treat COVID-19 is not available. Over the last few months a substantial amount of data about the structures of various key proteins and their recognition partners involved in the SARS-CoV-2 pathogenesis has emerged. These studies have not only provided the molecular level descriptions ofthe viral pathogenesis but also laid the foundation for rational drug design and discovery. In this review, we have recapitulated the structural details of four key viral enzymes, RNA-dependent RNA polymerase, 3-chymotrypsin like protease, papain-like protease and helicase, and two host factors including angiotensin-converting enzyme 2 and transmembrane serine protease involved in the SARS-CoV-2 pathogenesis, and described the potential hotspots present on these structures which could be explored for therapeutic intervention. We have also discussed the significance of endoplasmic reticulum α-glucosidases as potential targets for anti-SARS-CoV-2 drug discovery.

Ebselen as template for stabilization of A4V mutant dimer for motor neuron disease therapy.

Mutations to the gene encoding superoxide dismutase-1 (SOD1) were the first genetic elements discovered that cause motor neuron disease (MND). These mutations result in compromised SOD1 dimer stability, with one of the severest and most common mutations Ala4Val (A4V) displaying a propensity to monomerise and aggregate leading to neuronal death. We show that the clinically used ebselen and related analogues promote thermal stability of A4V SOD1 when binding to Cys111 only. We have developed a A4V SOD1 differential scanning fluorescence-based assay on a C6S mutation background that is effective in assessing suitability of compounds. Crystallographic data show that the selenium atom of these compounds binds covalently to A4V SOD1 at Cys111 at the dimer interface, resulting in stabilisation. This together with chemical amenability for hit expansion of ebselen and its on-target SOD1 pharmacological chaperone activity holds remarkable promise for structure-based therapeutics for MND using ebselen as a template.

An Engineered Microvirin Variant with Identical Structural Domains Potently Inhibits Human Immunodeficiency Virus and Hepatitis C Virus Cellular Entry.

Microvirin (MVN) is one of the human immunodeficiency virus (HIV-1) entry inhibitor lectins, which consists of two structural domains sharing 35% sequence identity and contrary to many other antiviral lectins, it exists as a monomer. In this study, we engineered an MVN variant, LUMS1, consisting of two domains with 100% sequence identity, thereby reducing the chemical heterogeneity, which is a major factor in eliciting immunogenicity. We determined carbohydrate binding of LUMS1 through NMR chemical shift perturbation and tested its anti-HIV activity in single-round infectivity assay and its anti-hepatitis C virus (HCV) activity in three different assays including HCVcc, HCVpp, and replicon assays. We further investigated the effect of LUMS1 on the activation of T helper (Th) and B cells through flow cytometry. LUMS1 showed binding to (1-2)mannobiose, the minimum glycan epitope of MVN, potently inhibited HIV-1 and HCV with EC50 of 37.2 and 45.3 nM, respectively, and showed negligible cytotoxicity with CC50 > 10 µM against PBMCs, Huh-7.5 and HepG2 cells, and 4.9 µM against TZM-bl cells. LUMS1 did not activate Th cells, and its stimulatory effect on B cells was markedly less as compared to MVN. Together, with these effects, LUMS1 represents a potential candidate for the development of antiviral therapies.

Crucial Role of Fluorine in Fully Alkylated Ladder-Type Carbazole-Based Nonfullerene Organic Solar Cells.

Two fused ladder-type nonfullerene acceptors, DTCCIC and DTCCIC-4F, based on an electron-donating alkylated dithienocyclopentacarbazole core flanked by electron-withdrawing nonfluorinated or fluorinated 1,1-dicyanomethylene-3-indanone (IC or IC-4F), are prepared and utilized in organic solar cells (OSCs). The two new molecules reveal planar structures and strong aggregation behavior, and fluorination is shown to red-shift the optical band gap and downshift energy levels. OSCs based on DTCCIC-4F exhibit a power conversion efficiency of 12.6%, much higher than that of DTCCIC-based devices (6.2%). Microstructural studies reveal that while both acceptors are highly crystalline, bulk heterojunction blends based on the nonfluorinated DTCCIC result in overly coarse domains, while blends based on the fluorinated DTCCIC-4F exhibit a more optimal nanoscale morphology. These results highlight the importance of end group fluorination in controlling molecular aggregation and miscibility.

Dithieno[3,2-b:2',3'-d]arsole-containing conjugated polymers in organic photovoltaic devices.

Arsole-derived conjugated polymers are a relatively new class of materials in the field of organic electronics. Herein, we report the synthesis of two new donor polymers containing fused dithieno[3,2-b:2',3'-d]arsole units and report their application in bulk heterojunction solar cells for the first time. Devices based upon blends with PC71BM display high open circuit voltages around 0.9 V and demonstrate power conversion efficiencies around 4%.

An Alkylated Indacenodithieno[3,2-b]thiophene-Based Nonfullerene Acceptor with High Crystallinity Exhibiting Single Junction Solar Cell Efficiencies Greater than 13% with Low Voltage Losses.

A new synthetic route, to prepare an alkylated indacenodithieno[3,2-b]thiophene-based nonfullerene acceptor (C8-ITIC), is reported. Compared to the reported ITIC with phenylalkyl side chains, the new acceptor C8-ITIC exhibits a reduction in the optical band gap, higher absorptivity, and an increased propensity to crystallize. Accordingly, blends with the donor polymer PBDB-T exhibit a power conversion efficiency (PCE) up to 12.4%. Further improvements in efficiency are found upon backbone fluorination of the donor polymer to afford the novel material PFBDB-T. The resulting blend with C8-ITIC shows an impressive PCE up to 13.2% as a result of the higher open-circuit voltage. Electroluminescence studies demonstrate that backbone fluorination reduces the energy loss of the blends, with PFBDB-T/C8-ITIC-based cells exhibiting a small energy loss of 0.6 eV combined with a high JSC of 19.6 mA cm-2 .

Enabling high-mobility, ambipolar charge-transport in a DPP-benzotriazole copolymer by side-chain engineering.

In this article we discuss the synthesis of four new low band-gap co-polymers based on the diketopyrrolopyrrole (DPP) and benzotriazole (BTZ) monomer unit. We demonstrate that the BTZ unit allows for additional solubilizing side-chains on the co-monomer and show that the introduction of a linear side-chain on the DPP-unit leads to an increase in thin-film order and charge-carrier mobility if a sufficiently solubilizing, branched, side chain is attached to the BTZ. We compare two different synthetic routes, direct arylation and Suzuki-polycondensation, by a direct comparison of polymers obtained via the two routes and show that direct arylation produces polymers with lower electrical performance which we attribute to a higher density of chain Furthermore we demonstrate that a polymer utilizing this design motif and synthesized via Suzuki-polycondensation ((l-C18)-DPP-(b-C17)-BTZ) exhibits exceptionally high and near balanced average electron and hole mobilities >2 cm2 V-1 s-1 which are among the highest, robustly extracted mobility values reported for DPP copolymers in a top-gate configuration to date. Our results demonstrate clearly that linear side chain substitution of the DPP unit together with co-monomers that allow for the use of sufficiently long or branched solubilizing side chains can be an attractive design motif for solution processable, high mobility DPP copolymers.

Fused dithienogermolodithiophene low band gap polymers for high-performance organic solar cells without processing additives.

We report the synthesis of a novel ladder-type fused ring donor, dithienogermolodithiophene, in which two thieno[3,2-b]thiophene units are held coplanar by a bridging dialkyl germanium. Polymerization of this extended monomer with N-octylthienopyrrolodione by Stille polycondensation afforded a polymer, pDTTG-TPD, with an optical band gap of 1.75 eV combined with a high ionization potential. Bulk heterojunction solar cells based upon pDTTG-TPD:PC(71)BM blends afforded efficiencies up to 7.2% without the need for thermal annealing or processing additives.

Thiophene fluorination to enhance photovoltaic performance in low band gap donor-acceptor polymers.

We report the first synthesis of a tetrafluorinated 4,7-bis(3,4-difluorothiophen-2-yl)-2,1,3-benzothiadiazole monomer and its polymerisation with dithieno[3,2-b:2',3'-d]germole by Stille coupling to afford a low band gap polymer with a high ionisation potential. Direct comparison to the non-fluorinated analogue demonstrates that fluorination results in an increase in ionisation potential with no change in optical band gap, and enhanced aggregation over the non-fluorinated polymer. These desirable properties result in a significant enhancement in OPV device performance in blends with PC(71)BM.

A selenophene-based low-bandgap donor-acceptor polymer leading to fast ambipolar logic.

Fast ambipolar CMOS-like logic is demonstrated using a new selenophene-based donor-acceptor polymer semiconductor. The polymer exhibits saturation hole and electron mobilities of 0.46 cm(2) /Vs and 0.84 cm(2) /Vs. Inverters are fabricated with high gains while three-stage ring oscillators show stable oscillation with an unprecedented maximum frequency of 182 kHz at a relatively low supply voltage of 50 V.